Currently available treatments for HIV are toxic and costly, and vulnerable to the emergence of drug resistance. Thus an intensive search for new treatments for HIV is underway. Among new treatments for HIV, immunotherapy is promising in part because it offers the potential to regenerate critical but weakened cellular immune responses against HIV. Since CD25+ regulatory T cells weaken cellular immune responses against HIV, immunotherapy that counteracts the effects of regulatory T cells during HIV infection merits development and testing. However, the development of targeted immunotherapy that counteracts regulatory T cells during HIV infection requires the identification of molecular mechanisms through which regulatory T cells suppress HIV-specific cellular immune responses. We have preliminary data suggesting that regulatory T cells suppress HIV-specific effector T cell proliferation via CTLA-4 signaling, and further that engagement of the regulatory T cell-associated cell surface molecule GITR can enhance HIV-specific effector T cell proliferation and perforin expression. To develop these findings further, and to delineate fully the mechanisms through which regulatory T cells undermine HIV-specific cellular immune responses, we will test the hypotheses that (1) CD25+ regulatory T cells suppress HIV-specific effector T cells through CTLA-4 signaling; (2) GITR engagement will enhance HIV-specific cellular immune responses by making effector T cells resistant to regulatory T cell suppression; (3) regulatory T cell dysfunction in HIV infection stems from abnormal CD40L signaling; and, (4) regulatory T cells foster HIV infection of CD4+ T cells. Determining the mechanisms through which regulatory T cells weaken HIV-specific cellular immune responses will shed new light on HIV pathogenesis, and may aid in the development of new immunotherapy against HIV. In addition to addressing important research questions, this proposal provides the applicant with ample opportunities to develop as an independent investigator. To capitalize on these opportunities, the applicant has designed a matching career development plan that includes hands-on laboratory training and a course in advanced immunology, all in the context of expert mentorship and strong institutional support. Thus, this proposal will support a promising young investigator who seeks to broaden his skill set as a clinician-scientist while determining how regulatory T cells weaken cellular immune responses againstHIV.